The giant red cells of Amphiuma were studied in preparation for their use in micropuncture studies. Amphiuma red cells can regulate their volume in anisotonic media. In hypotonic media the response resembles that of duck erythrocytes. However, the response in hypertonic media differs from that of duck erythrocytes and primarily involves an amiloride sensitive Na uptake. This difference in the hypertonic-induced transport process has important functional implications.